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Landscape of Transcriptional Deregulation in Lung Cancer Shu Zhang1,2,3,4, Mingfa Li1, Hongbin Ji2,3,4,5* and Zhaoyuan Fang2,3,4,6*

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Landscape of Transcriptional Deregulation in Lung Cancer Shu Zhang1,2,3,4, Mingfa Li1, Hongbin Ji2,3,4,5* and Zhaoyuan Fang2,3,4,6* Zhang et al. BMC Genomics (2018) 19:435 https://doi.org/10.1186/s12864-018-4828-1 RESEARCHARTICLE Open Access Landscape of transcriptional deregulation in lung cancer Shu Zhang1,2,3,4, Mingfa Li1, Hongbin Ji2,3,4,5* and Zhaoyuan Fang2,3,4,6* Abstract Background: Lung cancer is a very heterogeneous disease that can be pathologically classified into different subtypes including small-cell lung carcinoma (SCLC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and large-cell carcinoma (LCC). Although much progress has been made towards the oncogenic mechanism of each subtype, transcriptional circuits mediating the upstream signaling pathways and downstream functional consequences remain to be systematically studied. Results: Here we trained a one-class support vector machine (OC-SVM) model to establish a general transcription factor (TF) regulatory network containing 325 TFs and 18724 target genes. We then applied this network to lung cancer subtypes and identified those deregulated TFs and downstream targets. We found that the TP63/SOX2/ DMRT3 module was specific to LUSC, corresponding to squamous epithelial differentiation and/or survival. Moreover, the LEF1/MSC module was specifically activated in LUAD and likely to confer epithelial-to-mesenchymal transition, known important for cancer malignant progression and metastasis. The proneural factor, ASCL1, was specifically up-regulated in SCLC which is known to have a neuroendocrine phenotype. Also, ID2 was differentially regulated between SCLC and LUSC, with its up-regulation in SCLC linking to energy supply for fast mitosis and its down-regulation in LUSC linking to the attenuation of immune response. We further described the landscape of TF regulation among the three major subtypes of lung cancer, highlighting their functional commonalities and specificities. Conclusions: Our approach uncovered the landscape of transcriptional deregulation in lung cancer, and provided a useful resource of TF regulatory network for future studies. Keywords: Lung cancer, Transcription factors, Support-vector machines, Transcription regulatory network Background systematically uncover the molecular regulatory network Lung cancer is the leading cause of cancer-related deaths in contributing to lung cancer malignant progression. worldwide. Pathologically, lung cancers can be classified Transcription factors (TFs), known to be evolutionarily as small-cell lung carcinoma (SCLC) and non-small-cell conserved in orchestrating transcriptional gene regulation lung carcinoma (NSCLC), and the latter can be further networks, are the key players in contribution to a broad divided into lung adenocarcinoma (LUAD), lung squa- range of critical cellular physiological and pathological mous cell carcinoma (LUSC), and others such as processes, from normal development and physiological large-cell carcinoma (LCC). Among these lung cancer processes to diseases such as cancer [4–7]. Notably, mas- subtypes, LUAD, LUSC and SCLC are most prevalent, ter TFs bind to the corresponding promoter regions via accounting for about 40%, 25-30% and 10-15% respect- recognizing specific short sequence patterns (‘motifs’), and ively (https://www.cancer.org). Previous mechanistic regulate transcriptional expression of a series of target studies have greatly advanced our knowledge about genes, which thus control cell growth, proliferation and how lung cancer initiates, progresses and responds to differentiation. For instance, TFs such as PPARγ and C/ drug treatments [1–3]. However, it remains interesting to EBPα are key regulators of adipogenic differentiation [8]. Overexpression of TFs including OCT4, SOX2, KLF4 and MYC can reprogram fibroblasts to pluripotent stem cells * Correspondence: [email protected]; [email protected] [9, 10]. Nanog, another TF which is transcriptionally regu- 2State Key Laboratory of Cell Biology, Shanghai, China Full list of author information is available at the end of the article lated by OCT4 and SOX2, is also important for the © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. BMC Genomics (2018) 19:435 Page 2 of 13 maintenance of pluripotency [11]. Furthermore, TFs transformation and quantile normalization with voom [26], are the major driving forces of transdifferentiation and Pearson Correlation Coefficient (PCC) was computed for transition among different cell types [12]. Such TF regula- each pair of genes. Protein-protein interactions were down- tory programs also exist in cancer. For example, the loaded from the integrated EBI IntAct molecular inter- epithelial-to-mesenchymal transition (EMT) process, action database [27]. For each candidate gene, its PCCs mediated by key TFs such as SNAILs and bHLHs, is with the TF and TF-interacting proteins (‘neighbors’)were known to promote cancer malignant progression and computed, and the latter PCCs were summarized into three metastasis [13, 14]. The reprogramming factor, SOX2, quantiles (25% as Q1, 50% as M, 75% as Q3). The candidate has also been identified as a lineage-survival oncogene gene’s PCCs with the background genes were also calcu- in LUSC [15]. SOX2 and TP63 (the other known LUSC lated and summarized into these three quantiles. lineage TF) are both frequently amplified and crucial for LUSC development [15–17]. Recently, we have also OC-SVM model training and evaluation shown that, TP63 mediates the transdifferentiation from One-class support vector machine (OC-SVM) is a spe- LUAD to LUSC [18]. cial type of SVM model suitable for solving problems To systematically understand how transcription factors where high-quality training data is available for only one contribute to the malignant progression of lung cancer, class, and it has been widely used in single-class learning we employed a machine learning approach to build a and outlier detection [28, 29]. Here we used curated transcriptional regulatory network, based on curated regu- TF-target relations from the TRRUST database as the latory relations, motif distributions, protein-protein interac- positive training set [30], with synthetic negatives to tions (PPIs) and gene co-expression. With the application evaluate the model performance. The negative set was of this network in LUSC, LUAD and SCLC, we identified built with 1000 20kb random sequences scanned with those core TFs specific for each lung cancer subtype. We FIMO using the same setting. The correlation coefficient further described the landscape of TF deregulation in these data for synthetic genes were randomly chosen from real three major lung cancer subtypes. gene correlation coefficients. A random subset of 50,000 TF-target pairs were used for evaluation. The OC-SVM Methods model was trained using the libSVM R wrapper in the Lung cancer data sources and preprocessing e1071 package. With the radial basis kernel and a series The RNA-Seq FPKM and copy number data for TCGA of ‘nu’ (ranging between 1^-4 and 0.9) and ‘gamma’ LUAD and LUSC were downloaded from the UCSC Xena (2^-5, 2^-8, 2^-11), the performance of models were hub (http://xena.ucsc.edu/). The SCLC gene expression data assessed in terms of sensitivity and false positive rate were obtained from the paper-accompanied data [19]. Other (FPR) with 10-fold cross-validation. To achieve a high LUAD and LUSC data outside of TCGA were downloaded specificity that is essential for large-scale predictions from the NCBI GEO with accession number GSE81089. To where the candidate relations are huge (over 17,000,000), be concise, we refer to these LUAD and LUSC datasets out- we controlled the final model (nu=0.5, gamma=2^-5) at a side of TCGA as ‘LUAD2’ and ‘LUSC2’. For FPKM data, a relatively low FPR (0.002), sacrificing some sensitivity log-transformation was applied before downstream analyses (50%). This predicted 2,432,769 relationships between TFs of co-expression and differential expression. and protein-coding target genes, and ~5000 of them were likely to be false positives. Promoter sequences and motif analyses We obtained genomic sequences (UCSC hg19) from 10kb Identification of core TFs in lung cancer upstream to 10kb downstream of TSS for each Ensembl To ensure specificity on the lung cancer dataset, we fil- gene. Non-redundant TF motifs were from the JASPAR tered the predicted targets for individual TFs by enfor- database [20] and converted to MEME format. Additional cing two sequential steps: (i) the target gene must have motifs (NKX2-1 and ASCL1) were trained from the re- conditional co-expression with the TF (PCC>=0.5); (ii) ported TF binding peaks [21, 22], with the MEME-ChIP the target gene must have inter-correlations with at least pipeline [23]. Scanning of motifs along promoter sequences 1/6 of the other target genes (PCC>=0.5). Thus we en- was performed with FIMO (default p value threshold, 1e-4) sured both the TF-target correlations and the overall [24]. FIMO matches on each strand were categorized by inter-correlations among the targets. We next deter- upstream 10kb, 2kb, 500b and downstream 10kb, 2kb, mined the differential regulation of TF and targets in 500b, respectively. cancer versus normal tissue. A 2-fold expression change threshold (i.e. log2fc=1) and paired Student’s T test were Gene co-expression and network neighborhood analyses used to determine up- and down-regulated genes. The We downloaded the comprehensive tissue profiling data Benjamini-Hochberg method was used to control the from the GTEx project (version v6p) [25]. After logarithmic overall false discovery rates (FDR=0.1). All datasets were Zhang et al. BMC Genomics (2018) 19:435 Page 3 of 13 analyzed with these same threshold settings.
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